The purpose of this study is to examine the effect of diphenhydramine on sleep in children and adolescents with Autism Spectrum Disorder (ASD). Diphenhydramine is an anti-histaminergic agent with strong hypnotic properties. To accomplish this, the investigators will use a randomized double-blind placebo-controlled crossover 8-week study design to examine the effect of diphenhydramine on sleep physiology as assessed by polysomnography (PSG), actigraphy, circadian rhythm, and clinical measures.

Inclusion criteria:

Participants will meet the following

• Outpatients between 8 and 17 years of age at the time of consent
• Diagnostic and Statistical Manual, 5th edition (DSM-5) criteria for Autism Spectrum Disorder (ASD) on the basis of clinical evaluation, confirmed with the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule, 2nd Ed (ADOS-2) or the Childhood Autism Rating Scale, Second Edition (CARS-2).
• Males and females
• Availability of polysomnography (PSG) or actigraphy data
• Sleep disturbances as assessed using Children's Sleep Habits Questionnaire (CSHQ) with a score of 41 or higher
• care provider who can reliably bring participant to clinic visits, provide trustworthy ratings, and interacts with participant on a regular basis
• stable medications for at least 2 weeks, with the exception of Prozac which is required to be stable for at least 4 weeks
• no planned changes in psychosocial and biomedical interventions during the trial
• willingness to provide additional saliva samples and participate in key study procedures (i.e., safety measurements every visit, PSG at weeks 4 and 8, and wear the actigraphy watch for 2 weeks before the beginning of trial as well as during the 8 weeks of the trial).

Exclusion criteria:

Participants will be excluded if one or more of the following is met

• active suicidal ideation or DSM-5 diagnosis of schizophrenia, schizoaffective disorder, or psychotic disorder
• active medical problems: migraine, asthma, seizure disorder, significant physical illness (e.g., anaphylaxis, serious liver, renal, or cardiac pathology)
• evidence of a metabolic, or infectious etiology for the participant's autism on the basis of medical history, neurologic history, and available tests for inborn errors of metabolism and chromosomal analysis
• pregnant or sexually active females not using a reliable method of contraception (urinary tests for pregnancy will be employed in this study)
• individuals taking benzodiazepines, antiepileptic medications when prescribed for seizure disorder/epilepsy, melatonin and centrally-acting antihistamines
• history of hypersensitivity to diphenhydramine
• history of severe side effects from diphenhydramine
• history of adequate trial of diphenhydramine
• current use of any medications known to interact with diphenhydramine such as medications inhibiting CYP2D6
• taking anticholinergic agents (e.g., trihexyphenidyl, thioridazine).

We will submit de-identified clinical data to the NIMH Data Archive (NDA) data repository.